Objective: Report a unique onset of dystonia in family affected by tremor and segmental dystonia

Background: Background: A 66-year-old woman of Norweigan descent presented with several months of progressive blepharospasm, leading to functional blindness.  Botulinum toxin reduced  symptoms initially, but she soon developed lower face spasms, dysarthria, and hypophonia, without dysphagia, followed by jerky anterocollis and complaints of shortness of breath and increased respiratory rate. Imaging and testing was normal. Despite optimal medical and botulinum toxin treatment, she continued to progress, and bilateral GPi DBS was performed. Improvement with DBS is modest but she is undergoing continued adjustments. There was an extensive family history of dystonia: mother had onset in the neck in her 30s, with gradual spread to the spine, resulting in lateral spine posture and retrocollis; 3 maternal uncles with cervical dystonia; and daughter and niece with tremor.

Method: Case report and literature review with genetic testing.

Results: A dystonia genetic testing panel from Centogene (including a total of 88 genes tested through next-generation sequencing and copy number variant analysis) revealed a likely pathogenic variant:  a heterozygous frameshift mutation, c.1302_1303del (p.Asn435Hisfs*21), in the GNAL gene, which causes a shift in the reading frame starting at codon 435 in the protein product. The new reading frame ends in a stop codon 20 positions downstream. The predicted protein-length change affects a non-repetitive conserved region and is predicted to be likely pathogenic. This result is consistent with a genetic diagnosis of DYT-GNAL (formerly known as DYT25).The phenotype of DYT-GNAL is that of adult-onset segmental dystonia, typically with later onset (mean 32 years, range 7-54) with cervical and cranial dystonia that may also spread to the arms. There are over 30 different GNAL pathogenic variants, mostly heterozygous in nature, which are noted over the entire gene, with variable penetrance.

Conclusion: Adult-onset dystonia with familial occurrence and relatively rapid spread caudally is unusual and genetic causes must be explored.  Involvement of the respiratory muscles is unusual but can be disabling. DBS is a potential treatment option for long-term reduction of dystonia severity if medical treatment fails.  This case expands the phenotype (old age, diaphragm involvement, rapidity of spread) and genotype of DYT-GNAL.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/late-onset-familial-segmental-dystonia-with-novel-gnal-mutation/